Pregnancy- and lactation-associated osteoporosis: A case series of 6 patients

Rationale: There is still information about pregnancy- and lactation-associated osteoporosis, which is a type of osteoporosis that occurs in women with normal bone in the late pregnancy or lactation period. Patient concerns: Six cases of pregnancy- and lactation-associated osteoporosis diagnosed in our Endocrinology and Orthopedics Departments from January 2018 to June 2020 were retrospectively studied. The baseline characteristics, clinical features, laboratory findings, radiological manifestations, and follow-up outcomes were analyzed and compared with previous reports. Diagnoses: All six patients underwent magnetic resonance imaging scans and vertebral compressive fractures were detected in four patients. Outcomes: All six patients received conservative treatment and no surgical intervention. After a mean follow-up of 27.3 months (range 24–31 months), the symptoms of the six patients were significantly relieved, although four patients still had low back pain to varying degrees.


Introduction
Pregnancy-and lactation-associated osteoporosis (PLO) is a type of osteoporosis that occurs in women with normal bone in the late pregnancy or lactation period.It can manifest clinically as pain, bone loss, and even hip or back fracture. [1,2]Due to the relatively rare occurrence of PLO, many clinicians lack knowledge of PLO, which prevents many patients from receiving timely diagnosis and appropriate treatment and results in various negative outcomes, such as postpartum chronic low back pain, vertebral compression fracture and kyphosis deformity. [3]Also, as a result of the lack of awareness of the diagnosis and prognosis of PLO, some clinicians even perform unnecessary surgical interventions, like vertebroplasty, internal fixation or hip replacement, which causes irreversible iatrogenic damage and is a waste of medical resources. [4,5]herefore, it is extremely important to promote the knowledge and understanding of PLO among clinicians in the departments of orthopedics, endocrinology and obstetrics.However, there is currently limited information on PLO.A systematic review has been conducted to examine the risk factors, clinical manifestation, and treatment methods for this disease, [6] but it should be noted that there is still a lack of related research on PLO.This study describes the clinical features, treatment and prognosis of 6 PLO patients admitted to our hospital and aims to enhance the understanding of this rare disease.

Study design
Patients diagnosed with PLO in our hospital from January 2018 to June 2020 were retrospectively studied.Enrolled patients were excluded if they had been diagnosed with other secondary osteoporotic diseases, like hyperparathyroidism, Cushing syndrome, and hyperthyroidism.Ethical approval was obtained from the ethics committee at our hospital.

Data collection
Baseline characteristics, individual medical history, medication history, family history, pregnancy and childbirth history, laboratory tests, and neonatal characteristics were recorded retrospectively.The detailed information was demonstrated in Table 1.

Bone mineral density measurement and diagnostic criteria
Dual-energy X-ray absorptiometry (DXA) examination of lumbar spine (L2-L4) was used for bone mineral density (BMD) measurement on a Norland XR-600 Bone Densitometer (Norland Medical System, Inc., Fort Atkinson, WI).All the examinations were performed on the same machine and software in the Radiology Department of our hospital.The diagnostic criteria were as follows: patients had osteoporotic fracture or low back pain in late pregnancy or early postpartum with a Z value of −2 or lower, as evaluated by a DXA examination of lumbar spine. [7]

Results
Six patients with an average age of 33.5 years (30-36 years), all of whom were of Han ethnicity, were included in this study.Their average height was 163 cm (range 157-171), average weight was 56.2 kg (range 47-73), and average body mass index was 21.3 kg/m 2 (range 17.4-28.5).Among the common risk factors previously reported in the literature, 2 patients had a family history of osteoporosis, none of the patients had a history of smoking, a history of prepregnancy fracture, or a history of oral anticoagulant and glucocorticoid use (Table 1).
All patients were naturally conceived and had no history of assisted reproduction.Five patients had onset during the first pregnancy and 1 patient during the second pregnancy.The fetal sex was 2 males and 4 females.Five were breastfed postoperatively (Table 2).
All the cases presented as back pain, and the average visual analog scale score was 7.0 (range 4-10 points).The onset of pain in 6 patients was within the third trimester and 3 months postpartum.The detailed information is shown in Table 3.

BMD and radiographic features
The average Z-score obtained from the DXA measurement of lumbar spine BMD was −2.90 (range −4.37 to 1.34).All 6 patients underwent magnetic resonance imaging (MRI) examination, and four of them had vertebral compression fractures.The main feature of MRI images of the patients was a strip-shaped abnormal signal area under the upper endplate of the vertebral body, with low T1 phase signal and high T2 fat-suppressed phase signal.Fractures were mainly distributed in the thoracolumbar region (Fig. 1), and the 4 patients with vertebral compression fractures had multiple vertebral fractures with at least 2 levels and at most 9 levels.

Treatment and prognosis
All patients received conservative treatment and no surgical intervention.Oral calcium and vitamin D were administered to all 6 patients as baseline treatment and 4 patients were required to cease breastfeeding by doctor's advice.Two patients received short-term salmon calcitonin, 1 patient received teriparatide, and 1 patient received bisphosphonates.During the mean follow-up period of 27.3 months (range 24-31), the symptoms were obviously relieved in all patients, but 4 patients still had low back pain to varying degrees.One patient carried her second pregnancy to term without suffering from PLO again.

Discussion
Since PLO was first reported by Nordin in 1955, little epidemiological data on PLO has been reported. [8]Smith [9] reported that the incidence of PLO was approximately 4-8 cases per million persons.A previous systematic review of 338 cases worldwide revealed that the average age of PLO patients was 35.7 years old and the average body mass index was 22.2 kg/m 2 .Ninetytwo percent of patients developed clinical symptoms between 3 months prior and postdelivery. [6]n recent years, case reports and case series of PLO have gradually increased due to increasing awareness of this disease, but there is still little documented research PLO in China.The authors of these reports speculate that there might be a potentially higher incidence of PLO in China due to the adherence of Chinese people to the traditional custom of postpartum confinement. [10]Postpartum confinement means that the mother must strictly rest in a sealed room at home for 1 month immediately after giving birth.During the postpartum confinement period, the mother is not allowed to go out or open the window for ventilation.In Chinese traditional practice, postpartum confinement could help women recover better.However, the lack of exposure to ultraviolet sunlight may have a negative effect on the synthesis of vitamin D and bones, and increase the incidence of PLO. [11]any studies have shown that PLO is a multifactorial disease with unclear pathogenesis.It has been suggested that genetic and endocrine factors play an important role in the development of PLO.[14] Low-estrogen status after long-term anorexia, stress, excessive exercise and even premature ovarian failure, have been documented to be correlated with PLO. [15]Some studies have shown that increased calcium requirement for fetal skeletal development may also contribute to the development of PLO.At the end of pregnancy, fetal bone formation consumes about 30 grams of calcium, and more than 80% of calcium deposition occurs in the last trimester, which causes a sharp loss of maternal calcium and might lead to PLO during this period. [16,17]20] Fractures may occur in patients with severe PLO, and the most commonly involved site is the lumbar or thoracic spine region. [21,22]MRI is the most important examination to establish a definitive diagnosis.A typical MRI feature is strip-shaped abnormal signal area adjacent to the endplate in hypointense T1 and hyperintense T2 fat-suppressed phase. [23]It should be noted that different from postmenopausal osteoporotic fractures, PLO vertebral fractures often involve multiple vertebral fractures.In the present study, all PLO patients suffered vertebral fractures involving multiple vertebral fractures.This is consistent with the results of a previously published systematic review, reporting an average of 4.4 vertebral fractures among the 155 enrolled patients. [6]In view of this imaging feature, it is recommended that all PLO patients with vertebral fractures routinely undergo both lumbar and thoracic MRI examinations at the same time to rule out concurrent thoracolumbar fractures.
At present, there is still no consensus on the treatment of PLO, and the treatment protocol is mainly referred to that of postmenopausal osteoporosis.It is generally accepted that breastfeeding should be discontinued immediately after the establishment of a PLO diagnosis.Individualized drug treatment should be provided according to pain severity, bone density, bone remodeling markers, and prepregnancy plan. [24]Currently, the commonly used drugs include calcium and vitamin D, calcitonin, bisphosphonate, teriparatide, and denosumab, etc. Calcium and vitamin D can still be used as basic treatment.For patients with severe pain, calcitonin drugs can be considered due to its better analgesic effect in the short-term. [25]Bisphosphonate  has been widely used in the treatment of postmenopausal osteoporosis.However, since the drug will deposit in the bone tissue for a long time due to its long half-life, it remains unclear whether bisphosphonate will have an impact on the fetus during the second pregnancy.Therefore, for patients who may choose to have a second pregnancy, bisphosphonate should be carefully used. [26,27]Teriparatide has a shorter half-life compared with bisphosphate and has been reported to have good clinical effect on PLO. [28,29]Denosumab is also widely used and has achieved good results in the treatment of PLO.Although its half-life is longer than that of teriparatide, it is more convenient to use and has better compliance. [30]lthough the symptoms in all 6 patients were relieved at the last follow-up date in this study, there were still 4 patients with residual low back pain of varying degrees, suggesting that the symptoms of PLO may take a long time to disappear.Kyveritakis evaluated the clinical prognosis of PLO patients during a 6-year follow-up period, and found that 58% of the patients needed more than 3 years for the complete relieve of clinical symptoms, and about 1/4 of the patients suffered refracture.These findings indicate that PLO may not be a simple self-limiting disease, and requires appropriate therapy. [21]

Conclusion
PLO tends to occur in older and thinner women with clinical manifestations of varying severity.MRI often reveals multiple vertebral compressive fractures.The prognosis with conservative treatment is good, but complete relief may take a long time.

Figure 1 .
Figure 1.(A) The lateral X-ray film of the patient shows the compression change in L2 vertebral body on admission.(B) CT images reveals compression change and abnormal density in the L2 vertebral body on admission.(C) T1-weighted MRI shows abnormal low signal changes in the L2 vertebral body, lower edge of L5 vertebral body, and upper edge of S1 vertebral body on admission.(D) T2-weighted fat-suppressed MRI shows abnormal high signal changes in the L2 vertebral body, lower edge of L5 vertebral body, and upper edge of S1 vertebral body on admission.(E) After 3 months of conservative treatment, T1-weighted MRI shows that the abnormal signal in the affected vertebral body disappeared; (F) after 3 months of conservative treatment, T2-weighted fat-suppressed MRI shows that the abnormal signal in the affected vertebral body has disappeared.CT = Computer Tomography, MRI = magnetic resonance imaging.
Department of Endocrinology, 960 Hospital of PLA, Jinan, Shandong, People's Republic of China, b Department of Orthopedics, 960 Hospital of PLA, Jinan, Shandong, People's Republic of China, c Department of Obstetrics, 960 Hospital of PLA, Jinan, Shandong, People's Republic of China.
The authors have no conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.Ethical approvals were obtained from the Ethic committee of 960 Hospital of PLA. a

Table 2
Pregnancy and delivery characteristics.

Table 3
Clinical features.